EP0133887A1 - Dérivés de rifampicine solubles dans l'eau - Google Patents
Dérivés de rifampicine solubles dans l'eau Download PDFInfo
- Publication number
- EP0133887A1 EP0133887A1 EP84106938A EP84106938A EP0133887A1 EP 0133887 A1 EP0133887 A1 EP 0133887A1 EP 84106938 A EP84106938 A EP 84106938A EP 84106938 A EP84106938 A EP 84106938A EP 0133887 A1 EP0133887 A1 EP 0133887A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- compound
- formula
- hydrogen
- methyl
- defined above
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/08—Bridged systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Definitions
- Rifampicin i.e. 3-[[(4-methyl-1-piperazinyl)imino]me- thviyrifamycin, is a widely known antibacterial agent which shows a broad antibacterial spectrum and is used world-wide as the first choice agent in the treatment of tuberculosis and in many countries also for the treatment of other infectious diseases.
- the dosage forms containing rifampicin available on the market are limited to those designed for oral administration (capsules and syrups) (see Martindale, “The Extrapharmacopeia”, 28th Edition, The Pharmacological Press - London (1982), p.1582 ) and in some countries also to phlebo formulations for i.v. infusions (see G. Perna, F. Natale, "Intravenous use of rifampicin in tuberculous diseases", Clin. Ter. 90, 63-73 (1979).
- the phlebo formulations have been employed for clinical use only for the treatment of severely ill patients and the intravenous treatment is changed to the oral administration as soon as possible to avoid the possible development of undesired side-effects connected with this route of administration.
- the water solubility of the new rifampicin derivatives makes the new compounds particularly suitable for a formulation for intramuscular use.
- aqueous formulations of the new rifampicin derivatives of formula I are particularly suitable for intramuscular administration, they could be employed also for other administration routes when a water soluble rifampicin is required.
- aqueous formulations of the new compounds could be utilized advantageously for pediatric droplets in case of oral administration, or for intraarticular administration in the treatment of rheumatoid arthritis and allied pathologic conditions. It was recently reported in fact that some rifamycin salts proved to be very useful in this therapy (I. Caruso et al, Annals of Rheumatic Diseases, 1982, vol. 41, pp. 232-236) .
- the present invention provides for the new rifampicin derivatives, the process for their manufacture as well as the intermediates therein and the
- compositions containing the new compounds particularly the liquid pharmaceutical formulations suitable for intramuscular, intraarticular and oral administration.
- novel rifampicin derivatives of the present invention have the following formula wherein R stands for a (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy group and R 1 may represent hydrogen or an aliphatic acyl radical containing 2 to 4 carbon atoms.
- R stands for a (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy group
- R 1 may represent hydrogen or an aliphatic acyl radical containing 2 to 4 carbon atoms.
- the terms "(C 1 -C 3 )alkyl” and "(C 1 -C 3 )alkoxy” designate linear or branched alkyl and alkoxy radicals containing from 1 to 3 carbon atoms i.e.
- aliphatic acyl radical containing 2 to 4 carbon atoms is intended to indicate essentially acetyl, propionyl, butyryl, and isobutyryl radicals.
- a preferred group of compounds of the invention comprises those compounds of formula I wherein R is methyl, ethyl or ethoxy and R i is hydrogen or acetyl.
- a most preferred group of compounds of the invention comprises those compounds of formula I wherein R is methyl and R 1 is hydrogen or acetyl.
- the compounds of the present invention can not be prepared in acceptable yields and free from undesired by-products through direct acylation of rifampicin and all the experiments carried out changing the acylating agents and the reaction conditions failed to give the desired results.
- a new synthetic approach to the preparation of these compounds had to be studied which led the inventors to set up the following process which is summarized in Scheme I below (wherein the symbol Me represents CH 3 -, i.e. a methyl group):
- the compounds of the present invention are prepared starting from the quinone (oxidized form) of rifampicin (the compound of formula II) which is reacted, according to step A) above, with a suitably selected acyl halide of formula RCOX wherein R is as defined before and X stands for chlorine or bromine.
- RCOX acyl halide of formula RCOX wherein R is as defined before and X stands for chlorine or bromine.
- This first step of the reaction is conveniently carried out in a polar or not polar aprotic organic solvent which does not negatively interfere with the reaction course.
- a polar or not polar aprotic organic solvent which does not negatively interfere with the reaction course.
- examples of such a solvent are tetrahydrofuran, dioxane, methylene chloride, chloroform, carbon tetrachloride and like solvents.
- a hydrogen halide acceptor is required to combine with the hydrogen halide which forms during the reaction.
- a tertiary organic nitrogen base at least in equimolar proportion to the acyl halide reactant, is generally employed.
- Tri-(lower alkyl)amines e.g. triethylamine, pyridine, picolines, collidines and the like can suitably be employed as hydrogen halide acceptors. When pyridine, picolines or collidines are employed, they can be used in high excess and act therefore also as the reaction solvent.
- This first step of the reaction may be run at a temperature between -25°C and room temperature, but preferably between -20°C and +10°C and most preferably between -5°C and 5°C.
- reaction is complete in a few hours; anyway, the course of the reaction can easily be monitored by checking the disappearance of the starting compound of formula II by means of thin layer chromatography.
- the intermediate compounds of formula III can be recovered from the reaction mixture by conventional techniques, which involve separation of the quaternary ammonium salt by filtration, concentration of the filtrate to a small
- the obtained intermediate can be further purified by crystallization from a suitable crystallization solvent.
- step B) the obtained 8-acyl quinone intermediate of formula III is reduced to the corresponding hydroquinone form, thus yielding the compounds of formula I wherein R is as desired and R1 is hydrogen.
- Reduction of the quinone to the hydroquinone is accomplished by means of ascorbic acid which is known in the rifamycin chemistry to be capable of carrying out said reduction without affecting the other groups of the rifamycin molecule.
- the reduction reaction which takes a few minutes to be complete, is conveniently carried out at room temperature.
- the reaction is generally carried out in the presence of water and a suitable organic solvent, miscible or only partially miscible with water, which would not be affected by the presence of the mild reducing agent.
- reaction conditions suitable for the step C) acylation correspond moreorless to those described above for step A). Also in this case the reaction requires the use of a hydrogen halide acceptor and of a polar aprotic organic solvent which does not interfere unfavorably with the reaction course.
- the end product is then recovered by conventional techniques and purified by crystallization from a suitable crystallization solvent.
- Triethylamine (3.5 ml, about 25 mmole) is added at 0°C with stirring to a solution of 1,4-dideoxy-1,4-dihydro-3-[[(4-methyl-1-piperazinyl)iminolmethyl]-1,4-dioxorifa- mycin (16.4 g, 20 mmole) in anhydrous tetrahydrofuran (500 ml). Afterwards a solution of acetyl chloride (1.78 ml, 25 mmole) in anhydrous tetrahydrofuran (150 ml) is added dropwise at -5°C with stirring.
- a solution of L-(+)-ascorbic acid (3.52 g, 20 mmole) in water (800 ml) is added at room temperature with stirring to a solution of the compound of example 1 (8.6 g, 10 mmole) in ethyl acetate (800 ml).
- the reaction mixture is kept at room temperature for 30 minutes, afterwards the aqueous layer is separated and the organic phase is reextracted with water (800 ml).
- the aqueous layers are combined and washed with ethyl acetate (400 ml), then treated with 0.5 M phosphate buffer pH 7.38 up to pH 7.2 and extracted with methylene chloride (3 x 500 ml).
- the compound of the title is prepared by following substantially the same procedure as in the foregoing Example but starting from the compound of Example 2. Yield: 62%.
- Triethylamine (0.28 ml, about 2 mmole) is added at 0°C to a stirred solution of the compound of example 4 (1.73 g, 2 mmole) in methylene chloride (170 ml). Afterwards, a solution of acetyl chloride (0.14 ml, 2 mmole) in anhydrous tetrahydrofuran (1.5 ml) is added dropwise at - 20°C with stirring. The reaction mixture is kept 1 hour at 0°C and 3 hours at room temperature, then it is extracted with water (200 ml). The organic layer is separated, dried over CaCl 2 and concentrated to a small volume.
- the compounds of the present invention show a marked solubility in water as well as in mixtures of water with other pharmaceutically acceptable solvents miscible with water.
- solubility of the compounds of the present invention in comparison with rifampicin was assayed in water containing 2% ascorbic acid (solution A) and in water containing 2% ascorbic acid and 10% propylene glycol (solution B) and the pH of the resulting solutions was recorded.
- the results obtained show that while rifampicin solubility in either solutions is less than 50 mg/ml with a pH of about 3.5-3.6, the solubility of the compounds of the present invention and the pH of the obtained solutions are much higher.
- the compound of example 4 has a solubility of 100 mg/ml with a pH of 4.0 in solution A and of 150 mg/ml with a pH of 4.2 in solution B, while the compound of Example 7 has a solubility of more than 300 mg/ml in solution A with a pH of 4.5.
- the pharmaceutical liquid preparations for oral, intramuscular or intraarticular use containing a compound of formula I as the active ingredient will contain it in amounts which are consistent with a suitable posology and with the solubility properties of the particular compound employed.
- compositions are those prepared in the form of dosage units, i.e. measured volumes of liquid compositions, containing from about 50 to about 1000 mg and preferably from about 150 to about 500 mg of a compound of formula I per unit.
- the solvents which may be employed for the liquid preparations of the present invention are generally water or mixtures of water and polyhydric aliphatic alcohols such as ethyl alcohol, polyethylene glycol of the liquid series and propylene glycol. Besides the antibacterially active ingredient, additional substances may be added to the composition to improve or safeguard the quality of the product.
- the pharmaceutical liquid preparations of the present invention may contain
- liquid compositions of the present invention may contain also other active ingredients.
- active ingredients can include, for example, other water-soluble antibacterial agents which, when associated to rifampicin, may give rise to a synergistic effect, and, when preparations for intramuscular or intraarticular use are desired, local anesthetics and analgesic agents.
- compositions can be prepared by techniques known in the art for the preparation of solutions for oral use or sterile injectable compositions (see for instance Remington's Pharmaceutical Sciences, 13th Ed., M ack Publishing Co. Easton, Pennsylvania).
- suitable dosage units for extemporaneous intramuscular use may be prepared by dissolving the content of a vial of lyophilized material containing 300 mg of the compound of Example 4 in 3 ml of sterile water for injection containing 2% ascorbic acid or the content of a lyophilized vial consisting of 500 mg of the compound of Example 5 in 4 ml of sterile water for injection containing 15% propylene glycol and 2% ascorbic acid.
- dosage units for extemporaneous intramuscular use may be prepared by dissolving the content of a vial of lyophilized or powdered active principle of the invention (e.g. 315 mg of the compound of example 4 or 320 mg of the compound of example 5 in admixture with 10% ascorbic acid) in sterile water for injections (e. g . 3.5 ml for 315 m g of the compound of example 4 or 4 ml for 320 mg of
- polypropilene glycol e.g. 3 ml for 315 mg of the compound of example 4 or 3.5 ml for 320 mg of the comopund of example 5.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AT84106938T ATE29136T1 (de) | 1983-07-04 | 1984-06-17 | Wasserloesliche rifampicinderivate. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8318072 | 1983-07-04 | ||
GB838318072A GB8318072D0 (en) | 1983-07-04 | 1983-07-04 | Water-soluble rifampicin derivatives |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0133887A1 true EP0133887A1 (fr) | 1985-03-13 |
EP0133887B1 EP0133887B1 (fr) | 1987-08-26 |
Family
ID=10545208
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP84106938A Expired EP0133887B1 (fr) | 1983-07-04 | 1984-06-17 | Dérivés de rifampicine solubles dans l'eau |
Country Status (17)
Country | Link |
---|---|
US (1) | US4585589A (fr) |
EP (1) | EP0133887B1 (fr) |
JP (1) | JPS6036490A (fr) |
KR (1) | KR910005847B1 (fr) |
AT (1) | ATE29136T1 (fr) |
AU (1) | AU558707B2 (fr) |
CA (1) | CA1212670A (fr) |
DE (1) | DE3465597D1 (fr) |
DK (1) | DK157875C (fr) |
ES (1) | ES533957A0 (fr) |
GB (1) | GB8318072D0 (fr) |
HU (1) | HU190576B (fr) |
IE (1) | IE57930B1 (fr) |
IL (1) | IL72234A (fr) |
NZ (1) | NZ208757A (fr) |
PH (1) | PH20342A (fr) |
ZA (1) | ZA844661B (fr) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4916126A (en) * | 1987-09-25 | 1990-04-10 | Ciba-Geigy Corporation | Diacyl derivatives of 4-(trialkylbenzyl)-piperazinyl compounds |
Families Citing this family (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8408924D0 (en) * | 1984-04-06 | 1984-05-16 | Dobfar Spa | 3-azinomethyl rifamycins |
US5180718A (en) * | 1989-03-02 | 1993-01-19 | Ciba-Geigy Corporation | Acyl derivatives of oxazolorifamycins |
WO1998021956A1 (fr) * | 1996-11-19 | 1998-05-28 | Georgetown University | Antagonistes d'hereguline et leurs procedes d'utilisation |
WO2003045319A2 (fr) * | 2001-11-21 | 2003-06-05 | Activbiotics, Inc. | Agents therapeutiques cibles et leurs utilisations |
US7137963B2 (en) * | 2002-08-26 | 2006-11-21 | Flowcardia, Inc. | Ultrasound catheter for disrupting blood vessel obstructions |
US7820652B2 (en) * | 2003-09-24 | 2010-10-26 | Activbiotics Pharma, Llc | Regimen for the administration of rifamycin-class antibiotics |
US20170176475A1 (en) * | 2014-04-11 | 2017-06-22 | Drexel University | Novel methods and kits for detecting a rifamycin, or derivative or analogue thereof |
Family Cites Families (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
FR208F (fr) * | 1964-07-31 | |||
GB1159267A (en) * | 1966-11-03 | 1969-07-23 | Lepetit Spa | Rifamycin Derivatives |
NL145554B (nl) * | 1967-06-07 | 1975-04-15 | Lepetit Spa | Werkwijze voor het bereiden van een 3-formylrifamycine sv-derivaat |
AR207762A1 (es) * | 1973-07-25 | 1976-10-29 | Archifar Ind Chim Trentino | Procedimiento para la preparacion de 3-((4-metil-1-piperazin-1-il)-imino)-metil-rifamicina sv o rifampicina |
GB1594134A (en) * | 1977-11-25 | 1981-07-30 | Holco Investment Inc | Rifamycins |
US4298692A (en) * | 1979-01-25 | 1981-11-03 | Ciba-Geigy Corporation | Fermentation process for producing a rifamycin derivative |
US4411896A (en) * | 1981-06-03 | 1983-10-25 | Ciba-Geigy Corporation | Rifamycins, their compositions and use as antibiotics |
-
1983
- 1983-07-04 GB GB838318072A patent/GB8318072D0/en active Pending
-
1984
- 1984-06-15 AU AU29411/84A patent/AU558707B2/en not_active Ceased
- 1984-06-17 DE DE8484106938T patent/DE3465597D1/de not_active Expired
- 1984-06-17 EP EP84106938A patent/EP0133887B1/fr not_active Expired
- 1984-06-17 AT AT84106938T patent/ATE29136T1/de not_active IP Right Cessation
- 1984-06-20 ZA ZA844661A patent/ZA844661B/xx unknown
- 1984-06-26 DK DK311484A patent/DK157875C/da active
- 1984-06-27 PH PH30892A patent/PH20342A/en unknown
- 1984-06-27 IL IL72234A patent/IL72234A/xx unknown
- 1984-06-29 US US06/626,358 patent/US4585589A/en not_active Expired - Fee Related
- 1984-07-02 JP JP59135371A patent/JPS6036490A/ja active Granted
- 1984-07-03 IE IE1693/84A patent/IE57930B1/en not_active IP Right Cessation
- 1984-07-03 HU HU842575A patent/HU190576B/hu not_active IP Right Cessation
- 1984-07-03 ES ES533957A patent/ES533957A0/es active Granted
- 1984-07-03 CA CA000457960A patent/CA1212670A/fr not_active Expired
- 1984-07-03 NZ NZ208757A patent/NZ208757A/en unknown
- 1984-07-03 KR KR1019840003836A patent/KR910005847B1/ko not_active IP Right Cessation
Non-Patent Citations (1)
Title |
---|
No documents have been disclosed * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4916126A (en) * | 1987-09-25 | 1990-04-10 | Ciba-Geigy Corporation | Diacyl derivatives of 4-(trialkylbenzyl)-piperazinyl compounds |
Also Published As
Publication number | Publication date |
---|---|
IL72234A (en) | 1987-09-16 |
DE3465597D1 (en) | 1987-10-01 |
EP0133887B1 (fr) | 1987-08-26 |
JPH0544467B2 (fr) | 1993-07-06 |
DK311484D0 (da) | 1984-06-26 |
ES8601949A1 (es) | 1985-11-01 |
IE57930B1 (en) | 1993-05-19 |
DK157875B (da) | 1990-02-26 |
DK311484A (da) | 1985-01-05 |
HU190576B (en) | 1986-09-29 |
ATE29136T1 (de) | 1987-09-15 |
NZ208757A (en) | 1987-08-31 |
IE841693L (en) | 1985-01-04 |
JPS6036490A (ja) | 1985-02-25 |
KR850001207A (ko) | 1985-03-16 |
IL72234A0 (en) | 1984-10-31 |
US4585589A (en) | 1986-04-29 |
ZA844661B (en) | 1985-04-24 |
ES533957A0 (es) | 1985-11-01 |
CA1212670A (fr) | 1986-10-14 |
PH20342A (en) | 1986-12-04 |
AU558707B2 (en) | 1987-02-05 |
DK157875C (da) | 1990-08-20 |
GB8318072D0 (en) | 1983-08-03 |
KR910005847B1 (ko) | 1991-08-05 |
AU2941184A (en) | 1985-01-10 |
HUT36128A (en) | 1985-08-28 |
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